Rapid stimulation of human dentate gyrus function with acute mild exercise Kazuya Suwabea,b,1, Kyeongho Byunb,c,1, Kazuki Hyodoa, Zachariah M. Reaghc,d, Jared M. Robertsc,d, Akira Matsushitae,f, Kousaku Saotomee, Genta Ochia, Takemune Fukuiea, Kenji Suzukie, Yoshiyuki Sankaie, Michael A. Yassab,c,d,2, and Hideaki Soyaa,b,2 aLaboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, 305-8574 Ibaraki, Japan; bSports Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), Faculty of Health and Sport Sciences, University of Tsukuba, 305-8574 Ibaraki, Japan; cDepartment of Neurobiology and Behavior, University of California, Irvine, CA 92697-3800; dCenter for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92697-3800; eCenter for Cybernics Research, University of Tsukuba, 305-8574 Ibaraki, Japan; and fDepartment of Neurology, Ibaraki Prefectural University of Health Sciences, 300-0394 Ibaraki, Japan Edited by Bruce McEwen, The Rockefeller University, New York, NY, and approved August 14, 2018 (received for review April 19, 2018) Physical exercise has beneficial effects on neurocognitive function, differentiating among similar experiences to keep stored memo- including hippocampus-dependent episodic memory. Exercise inten- ries distinct from one another (11). We recently reported that acute V_ sity level can be assessed according to whether it induces a stress moderate-intensity exercise (50% peak oxygen uptake [ O2peak]) response; the most effective exercise for improving hippocampal improves mnemonic discrimination performance for highly similar function remains unclear. Our prior work using a special treadmill items in a task that is thought to rely on DG-mediated pattern running model in animals has shown that stress-free mild exercise separation (12). Using the same experimental design, we con- increases hippocampal neuronal activity and promotes adult neuro- ducted two experiments to investigate whether even acute very genesis in the dentate gyrus (DG) of the hippocampus, improving light, stress-free exercise similarly improves hippocampal memory, spatial memory performance. However, the rapid modification, from and, if so, to identify the underlying neural mechanisms using mild exercise, on hippocampal memory function and the exact high-resolution fMRI of hippocampal subfields and cortical re- mechanisms for these changes, in particular the impact on pattern gions during task performance. separation acting in the DG and CA3 regions, are yet to be elucidated. In experiment 1, we assessed the effect of 10 min of acute mild V_ “ ” To this end, we adopted an acute-exercise design in humans, coupled exercise (30% O2peak; defined as very light by the American with high-resolution functional MRI techniques, capable of resolving College of Sports Medicine [ACSM]) on performance in the hippocampal subfields. A single 10-min bout of very light-intensity mnemonic discrimination task. We set the exercise duration exercise (30%V_ ) results in rapid enhancement in pattern sepa- to 10 min because our past work has shown that a minimum of O2peak ration and an increase in functional connectivity between hippocam- 10 min of exercise improves cognitive performance (13). Healthy SI Appendix pal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and young adults ( , Table S1) were assessed under two fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an in- Significance dividual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possi- Our previous work has shown that mild physical exercise can bly by increasing DG/CA3−neocortical functional connectivity. promote better memory in rodents. Here, we use functional MRI in healthy young adults to assess the immediate impact of physical exercise | hippocampus | episodic memory | pattern separation | a short bout of mild exercise on the brain mechanisms sup- functional MRI porting memory processes. We find that this brief intervention rapidly enhanced highly detailed memory processing and hysical exercise is an important lifestyle intervention for resulted in elevated activity in the hippocampus and the sur- NEUROSCIENCE Ppromoting mental health, including hippocampal-dependent rounding regions, as well as increased coupling between the memory. Wheel running has well-known effects on hippocampal hippocampus and cortical regions previously known to support neural plasticity and memory in rodents (1); however, the most detailed memory processing. These findings represent a effective exercise regimen (e.g., intensity level) for improving hip- mechanism by which mild exercise, on par with yoga and tai pocampal function remains an open question. Exercise intensity can chi, may improve memory. Future studies should test the long- be assessed according to whether it induces a stress response based term effects of regular mild exercise on age-related memory on the lactate threshold (LT). Our recent studies using an animal loss. model of exercise that utilizes controlled treadmill running to dis- tinguish stress-free mild exercise (below LT) from intense exercise Author contributions: K. Suwabe, K.B., M.A.Y., and H.S. designed research; K. Suwabe, K.H., A.M., K. Saotome, G.O., and T.F. performed research; Z.M.R., K. Suzuki, Y.S., and (above LT) have shown that mild exercise increases hippocampal M.A.Y. contributed new reagents/analytic tools; K. Suwabe, K.B., K.H., Z.M.R., J.M.R., neuronal activity (2) and promotes adult neurogenesis in the den- A.M., K. Saotome, and M.A.Y. analyzed data; and K. Suwabe, K.B., M.A.Y., and H.S. wrote tategyrus(DG)(3–5), improving spatial memory performance (6). the paper. Intriguingly, these effects were suppressed with intense exercise, i.e., The authors declare no conflict of interest. follow a hormetic dose–response profile (3–6). Based on this evi- This article is a PNAS Direct Submission. dence, we hypothesized that very light-intensity exercise can stim- Published under the PNAS license. ulate the human hippocampus, and improve episodic memory Data deposition: All neuroimaging data were deposited with XNAT CENTRAL and are through functional activation in the hippocampal network. available at https://central.xnat.org (Acute Mild Exercise). The fMRI scripts were deposited To test this hypothesis in humans, we used an acute-exercise on GitHub and are available at https://github.com/yassalab/afni_proc_py_pipeline. design based on our previous human studies (7–10), coupled with 1K. Suwabe and K.B. contributed equally to this work. high-resolution functional magnetic resonance imaging (fMRI) 2To whom correspondence may be addressed. Email: [email protected] or soya.hideaki.gt@ techniques, capable of resolving hippocampal subfields, to ex- u.tsukuba.ac.jp. amine the neural substrates of exercise-enhanced hippocampal This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. function. We specifically hypothesized that mild exercise will 1073/pnas.1805668115/-/DCSupplemental. enhance DG-mediated pattern separation, the process of Published online September 24, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1805668115 PNAS | October 9, 2018 | vol. 115 | no. 41 | 10487–10492 Downloaded by guest on September 27, 2021 experimental conditions, control (CTL) and exercise (EX), on the study and test sessions into one continuous session) of a separate days in randomized order (Fig. 1A). A within-subject mnemonic discrimination task in the MRI scanner within ∼5 min design was applied to increase power and reduce the effects of after a 10-min mild exercise session (SI Appendix, Fig. S1). We intersubject variability in the response to exercise. In the EX compared neural activity during the critical pattern separation condition, participants performed 10 min of very light-intensity contrast [lure correct rejections (CRs) minus lure false alarms exercise on a recumbent cycle ergometer, with an individualized (FAs)] based on prior study (18) between the EX and CTL ’ V_ load corresponding to 30% of the participant s O2peak.IntheCTL conditions. Moreover, we assessed functional correlations be- condition, participants sat quietly on the ergometer instead of tween hippocampal subfields and cortical regions using psycho- performing exercise. All other conditions were held constant. After physiological interaction (PPI) analysis. 10 min in the EX or CTL condition, participants performed the explicit version of the mnemonic discrimination task described Results previously (14, 15). During the study phase, participants were shown Physiological and Psychological Response to Acute Mild Exercise. In pictures of everyday objects and asked to indicate whether each both experiments, we first confirmed that mean heart rate (HR) at item was an indoor or an outdoor item. This was followed by a the end of the EX session was within the range of very light in- recognition test in which participants were asked to identify each tensity according to the ACSM guidelines (SI Appendix,TableS1). “ ” “ ” item as either old (targets: previously seen items), similar We measured salivary alpha amylase (sAA) and cortisol levels (lures: similar but not identical to previously viewed images), or throughout the experiment. A repeated measures two-way ANOVA “ ” new (foils: new items not previously seen). The lure stimuli varied for